Five novel mutations in the ADAR1 gene associated with dyschromatosis symmetrica hereditaria.
Five novel mutations in the ADAR1 gene associated with dyschromatosis symmetrica hereditaria.
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ADAR1 基因的五种新突变与遗传性对称性色素异常症相关
DOI：
10.1186/1471-2350-15-69
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发表时间：
2014-06-20
影响因子：
--
通讯作者：
Luo Y
中科院分区：
文献类型：
--
作者：
Liu Q;Wang Z;Wu Y;Cao L;Tang Q;Xing X;Ma H;Zhang S;Luo Y
背景遗传性皮肤色素异常症（DSH）是一种常染色体显性遗传性皮肤病，与ADAR 1基因突变有关。方法采用直接测序法对7个DSH家系的ADAR 1基因的所有编码外显子（包括邻近内含子、5′和3′非翻译区）进行突变筛查。结果分子遗传学研究检测到5个新突变（c.556C> T、c.3001C T、>c.1936_1937insTG、c.1065_1068delGACA和c.1601G> A），导致p.Gln186X、p.Arg1001Cys、p.Phe646LeufsX16、p.Asp357ArgfsX47和p.Gly471AspfsX30蛋白变化，以及先前报道的两种（c.2744C> T和c.3463C> T分别引起p.Ser915Phe和p.Arg1155Trp蛋白变化）。其中，我们发现外显子2最后一个核苷酸的c.1601GA取代损害了对内含子2剪接供体位点的识别，诱导了外显子2中190-bp缺失的异常转录，并导致受影响个体的ADAR 1 mRNA水平降低约50%。此外，与预测的结果一致，其他新的突变的表达模式进行了检测westernblot.ConclusionWe确定了五个新的和两个复发性突变的ADAR 1基因在7个中国家庭DSH和调查的潜在影响，在这项研究中的新突变。我们的研究扩展了ADAR 1突变的数据库，并首次证明了外显子-内含子连接处的外显子核苷酸对ADAR 1剪接的重要性。
BackgroundDyschromatosis symmetrica hereditaria (DSH) is an autosomal dominantly inherited skin disease associated with mutations of ADAR1, the gene that encodes a double-stranded RNA-specific adenosine deaminase. The purpose of this study was to investigate the potential mutations in ADAR1 in seven Chinese families with DSH.MethodsAll the coding exons including adjacent intronic as well as 5′ and 3′ untranslated region (UTR) of ADAR1 were screened by direct sequencing. Moreover, quantitative reverse-transcription polymerase chain (qRT-PCR) and Western blot were applied to determine the pathogenic effects associated with the mutations.ResultsMolecular genetic investigations detected five novel mutations (c.556C > T, c.3001C > T, c.1936_1937insTG, c.1065_1068delGACA and c.1601G > A resulting in p.Gln186X, p.Arg1001Cys, p.Phe646LeufsX16, p.Asp357ArgfsX47 and p.Gly471AspfsX30 protein changes, respectively) as well as two previously reported (c.2744C > T and c.3463C > T causing p.Ser915Phe and p.Arg1155Trp protein changes, respectively). Among them, we found that the substitution c.1601G > A at the last nucleotide of exon 2 compromised the recognition of the splice donor site of intron 2, inducing an aberrant transcript with 190-bp deletion in exon 2 and causing an approximately 50% reduction of ADAR1 mRNA level in affected individual. In addition, consistent with the predicted results, the expression patterns of other novel mutations were detected by Western blot.ConclusionWe identified five novel and two recurrent mutations of the ADAR1 gene in seven Chinese families with DSH and investigated potential effects of the novel mutations in this study. Our study expands the database on mutations of ADAR1 and for the first time, demonstrates the importance of exonic nucleotides at exon-intron junctions for ADAR1 splicing.
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影响因子：
10.3
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
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